Introduction

Adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) is a parent's nightmare. The disease is caused by a deficiency in an enzyme responsible for breaking down toxic metabolites that would otherwise kill lymphocytes. Untreated, infants develop recurrent infections and fail to put on weight; they rarely live past two.

But to scientists trying to establish proof of principle for gene transfer, ADA-SCID is a dream: only small amounts of gene correction are needed to restore immune function, tissues are easy to procure for genetic modification, and theoretically, treated cells should have a survival advantage over those that are not corrected. The attractiveness of ADA-SCID is so high, and its incidence so low (approximately one case per 100 000 births) that researcher Stuart Orkin once commented “more [gene transfer researchers would soon be] working on ADA deficiency than there are patients who have it.”

But there's a catch. Since the late 1980s, a relatively safe and effective enzyme replacement therapy – PEG-ADA – has been available for ADA-SCID patients. Denying PEG-ADA to children in gene-transfer trials would be unethical, because it would expose them to the risk of relapse. Yet concurrent treatment with PEG-ADA would have scientific costs: it would confound interpretation of the subjects' responses (if volunteers improved, how would investigators be able to tell whether this was owing to the gene transfer or the enzyme replacement?)and it would sustain uncorrected cells (thus dampening the potential therapeutic effects of gene transfer).

Throughout the 1990s, several teams attempted ADA-SCID gene transfer. Each, however, used concurrent enzyme replacement therapy and none produced clear therapeutic successes.